Abstract Protein misfolding and aggregation, leading to chronic inflammation, neuronal dysfunction and death are common hallmarks of age-related dementia and neurodegenerative diseases such as Huntington?s disease (HD) and Alzheimer?s disease (AD). HD is an inherited neurodegenerative disorder caused by poly-glutamine (polyQ) expansion in the mutant Huntingtin (mHtt) protein, causing misfolding and aggregation. The misfolded mutant mHtt protein forms toxic aggregates, often found in a complex with Tau, leading to neurodegeneration and chronic inflammation in the striatum and cortex. There are currently no therapies to delay disease onset or slow the progression of neurodegenerative diseases that address the underlying biochemical defect of protein misfolding and inflammation. Heat Shock Transcription Factor 1 (HSF1) is a critical neuronal stress-protective transcription factor. HSF1 activate genes encoding protein chaperones, autophagy components, neurotrophic factors and anti-apoptotic proteins and represses genes encoding pro- inflammatory factors and Tau, which contributes to pathology in many neurodegenerative diseases. While HSF1 activation has therapeutic potential in HD, AD and other neurodegenerative diseases, HSF1 levels are abnormally low in human HD and AD tissues and HSF1 neuroprotective target genes are improperly regulated. We discovered that expression of mHtt triggers the inappropriate degradation of HSF1 through a dysregulated pathway in cellular and mouse HD models and in HD patients. In this application we outline experiments to (1) decipher the molecular mechanisms by which HSF1 is inappropriately degraded in HD, determine the consequences of restoring HSF1 in cell function, and ascertain whether the same or distinct mechanisms underlie HSF degradation in Spinal Bulbar Muscular Atrophy (SBMA), a disease caused by poly-glutamine expansion in the Androgen receptor and (2) test whether restoration of HSF1 by genetic or pharmacological intervention has therapeutic potential in mouse HD models. Given that neurodegenerative diseases characterized by protein aggregation, chronic inflammation and inappropriate neuronal cell death have decreased levels of neuro-protective HSF1, understanding how HSF1 is degraded in HD could identify key mechanistic nodes for therapeutic intervention in HD and other age-related dementias and neurodegenerative diseases.